The mechanisms by which tobacco smoke cause chronic bronchitis and lung cancer are unknown. Clues are provided, however, by our recent findings showing that smoke directly induces mucin mRNA and mitogenesis in lung epithelial cells and that this is preceded by activation of Src kinase and phosphorylation of the EGF receptor (EGFr). Src kinase inhibitors abrogate smoke-induced EGFr phosphorylation, mucin transcription induction and mitogenesis. EGFr kinase inhibitors abrogate smoke-induced EGFr phosphorylation and mitogenesis but only partially block mucin transcriptional upregulation. This leads us to hypothesize that smoke activates a branched signaling pathway emanating from Src kinase. One arm of the pathway is EGFr-dependent and is sufficient to account for smoke-induced mitogenesis; the other is EGFr-independent and its effects summate with those of the other branch to mediate mucin transcription. The experiments described in this proposal will provide information regarding both the EGFr-dependent and -independent signaling pathways. In experiments described under Specific Aim I, we will identify EGFr-interacting elements of the smoke-signaling pathway leading to (a) mucin induction and (b) mitogenesis. In experiments described under Specific Aim II, we will identify Src-interacting elements of the smoke signaling pathway leading to (a) mucin induction and (b) mitogenesis. In experiments described under Specific Aim III, we will identify components of smoke responsible for activating (a) mucin induction and (b) mitogenesis. The results of these studies should reveal control points amenable to inhibition by pharmacological agents.